Citations

Abstract It has been suggested recently that, although fluoride therapy may decrease the occurrence of vertebral fractures, it could increase the risk of hip fractures. To evaluate this possibility, we combined retrospective data from five medical centers that have had a large experience with this therapeutic regimen. In 416 osteoporotic patients who were followed for more than 1,000 patient-years of fluoride treatment, there were 17 nontraumatic hip fractures. This incidence of 1.6% per year is similar to the incidence, 1.9% per year, for 120 of the patients in this series who had been followed prospectively for 3 years prior to initiation of fluoride therapy. The expected incidence for women of the same age in the general community is 0.5% per year. Thus, untreated osteoporotic women are at increased risk for hip fracture, but treatment with fluoride seems neither to decrease nor to increase the incidence of hip fracture substantially.

Abstract Although levels of serum immunoreactive parathyroid hormone (iPTH) increase with age in women, this could be caused by retention of non-biologically active PTH fragments by the aging kidney. In 102 normal women, aged 30 to 89 yr, serum iPTH increased with age by 58% (r = 0.33, p < 0.001) with antiserum GP-1M (which has midmolecule specificity) and 43% (r = 0.32, p < 0.001) with antiserum CH-12M (which may have whole molecule specificity); urinary cAMP/GFR excretion increased by 29% (r = 0.22, p < 0.05). The results of these assays were validated by comparison with serum levels of biologically active PTH (BioPTH) in immunoextracts of serum followed by renal adenylate cyclase assay in a selected subgroup of 25 of the women. Serum BioPTH correlated with serum iPTH assessed by antiserum GP-1M (r = 0.48, p < 0.05) and antiserum CH-12M (r = 0.48, p < 0.05) but not with urinary cAMP. The data are consistent with an increase of parathyroid function with aging: clearly, we do not find decreased parathyroid function as would be expected if age-related bone loss was not mediated, in part, by PTH.

Abstract In order to characterize an avian parathyroid hormone gene, a λgt10 cDNA library constructed from chicken parathyroid gland mRNA was screened with a human preproparathyroid hormone (preproPTH) cDNA probe. Nucleotide sequence analysis of three independent clones confirmed that they encoded chicken preproPTH. This analysis, complemented by primer extension and Northern blot analysis of mRNA, demonstrated a 5′-untranslated region for chicken preproPTH of 127 nucleotides, a coding region of 357 nucleotides, and a 3′-untranslated region of approximately 2500 nucleotides. The coding sequence predicts a mature chicken PTH of 88 amino acids in contrast to the 84 amino acids of the mammalian hormones. Comparison of the avian and the mammalian hormones shows striking homology in the region of amino acids 1–32. The middle and carboxyl-terminal portions of chicken PTH, however, differ considerably from the mammalian hormones and include deletions of sequences conserved in mammalian PTH and insertions of novel peptide sequences. Comparison of the avian and mammalian structures suggests potential alterations of the mammalian sequences that may lead to altered bioactivity and/or hormone metabolism.

Abstract Estrogen (E) therapy and administration of oral contraceptives (OC) reportedly increase plasma calcitonin (CT) concentrations in women, effects said to mediate in part the beneficial actions of E on bone. To further examine this theory, we tested the effects of three cycles of OC therapy in 12 young women, comparing them to 10 healthy women before and after three normal menstrual cycles. We also determined the effects of 3 months of E therapy (ethinyl estradiol, 20 μg/day, 25 of 30 days) in 14 healthy postmenopausal women, using a crossover design (studied after 3 months with and 3 months without E). We determined CT by radioimmunoassay (antiserum G-1701) in whole plasma (iCT) and silica cartridge extracts of plasma (exCT) after overnight fasting, after calcium (Ca) infusion (2 mg Ca/kg over 5 minutes), and during a normal day at 0800, 1200, 1700, and 2000 h. In no control study was there a significant diurnal change in iCT or exCT, and neither OC nor E therapy altered this. Similarly, OC administration did not affect basal CT levels or the normal iCT and exCT responses to Ca infusion. E therapy induced expected changes in serum Ca, phosphorus, and alkaline phosphatase and urinary Ca and cAMP excretion; basal and diurnal plasma exCT levels were decreased significantly, consonant with the decrement in serum Ca. E did not alter normal iCT and exCT responses to Ca infusion. Thus, administration of either OC or E has no stimulatory effect on CT secretion, which suggests that the beneficial actions of E on bone are not mediated through CT-induced inhibition of bone resorption. Interaction of E with CT action at the cellular level is not excluded by these findings, but there are no data to support such a proposal.

Abstract We sought to determine if any protective effect of dietary calcium (Ca) or Ca supplements on bone could be at least partially mediated by increased calcitonin (CT) secretion. First we studied 10 healthy premenopausal women (median age, 35.5 years) who were randomized to high or low dietary Ca intake (1752 versus 391 mg elemental Ca per day) for 2 weeks and then crossed over. At the end of each dietary period, blood was drawn on 1 day at 0800, 1200, 1700, and 2000 h to assess diurnal variation of plasma CT levels. CT secretory reserve was assessed on the next day by Ca infusion (2 mg Ca per kg body weight over 5 minutes). Next, we studied 10 healthy premenopausal women who took a low-Ca diet (∼ 400 mg Ca per day) for a 2 week control period. The women were then randomized to high- or low-Ca intake [400 mg dietary Ca ± 1500 mg Ca per day (as supplemental CaCO3)] and then crossed over. At the end of each study period, the diurnal variation in CT was tested on day 1; the CT secretory reserve was assessed on day 3 by an oral Ca load (500 mg as CaCO3)] and on day 5 by Ca infusion. Plasma immunoreactive CT was measured in whole plasma (iCT) and after silica extraction (exCT), predominantly monomeric CT. Neither increased dietary Ca nor Ca supplements affected the diurnal levels of iCT or exCT or augmented plasma CT responses to an oral Ca load. Furthermore, there was no change in secretory reserve for iCT or exCT after Ca infusion. We conclude that short-term Ca administration, in the form of dietary Ca or Ca salts, at the extremes of normal dietary intake and in doses normally used to treat osteoporosis, respectively, does not affect CT secretion in healthy premenopausal women. It seems unlikely that any potential beneficial effects of ingested Ca on the skeleton in women are mediated by CT.

Abstract To determine whether Colles' fracture, generally considered a manifestation of postmenopausal osteoporosis, is associated with a decrease in bone density at the site of fracture, we measured bone mineral density of the ultradistal radius (UDR-BMD) by single-photon absorptiometry with computer-assisted image processing. In 119 normal women (ages 22–92 years), UDR-BMD decreased by 17% between ages 30 and 75 years. From UDR-BMD measurements in these normal women and in 40 women (ages 53–80 years) with Colles' fracture alone, a population-based analysis was made to estimate fracture risk at different values of UDR-BMD. Colles' fracture was uncommon at UDR-BMD > 0.40 g/cm2 (the “fracture threshold”). As bone density decreased below this level, fractures became more frequent (a “gradient of risk”).

Abstract The effects of castration on bone histomorphometry and mineral homeostasis were compared in male and female rats. Measurements were performed 4 weeks after sham operation or gonadectomy. Orchiectomy produced increases in serum calcium and decreases in serum testosterone and androstenedione, whereas ovariectomy produced decreases in serum estradiol and testosterone. Orchiectomy did not alter static bone histomorphometric measurements of the tibial diaphysis, whereas ovariectomy increased cross-sectional and medullary areas, lowered endosteal tetracycline-labeled surface length, and markedly increased endosteal nonlabeled surface length. Orchiectomy decreased mean periosteal bone formation rate and mean periosteal bone apposition rate, whereas ovariectomy increased both measurements. Orchiectomy and ovariectomy markedly diminished trabecular area and trabecular surface length at the tibial metaphysis. Orchiectomy did not alter the number of osteoclasts per mm trabecular surface or the percentage of trabecular surface covered by osteoclasts, whereas ovariectomy increased both measurements. These findings indicate that gonadal hormones produce separate and distinct effects on bone metabolism as determined by histomorphometry in male and female rats.

Abstract The effects of fluoride at concentrations of 2.0 and 4.5 mM in drinking water on growth rate, vitamin D, water and mineral metabolism, bone histomorphometry, and osteoinduction of demineralized allogenic bone matrix (DABM) were compared in the rat. Whereas fluoride did not influence fluid intake or growth rate at the lower concentration, it increased fluid intake and inhibited growth rate at the higher concentration. Fluoride produced dose-related increases in serum fluoride and alkaline phosphatase but did not alter serum 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D. Serum calcium and phosphate were reduced by fluoride at concentrations of 2.0 mM but not 4.5 mM. Cancellous bone fractional area was increased by fluoride at 2.0 mM and was reduced by fluoride at 4.5 mM. Fluoride had no effect on cancellous bone surface length or the percentage surface lined by osteoblasts and osteoclasts. Fluoride increased medullary area and decreased the endosteal bone formation rate. Fluoride increased periosteal bone formation and apposition rates at concentrations of 2.0 mM but not 4.5 mM. Fluoride inhibited mineralization in DABM implants, and at the higher concentration, fluoride increased the formation of new bone matrix. These results indicate that in the rat, fluoride increases cortical and trabecular bone at therapeutic doses and reduces trabecular bone at toxic doses. The serum concentration of flouride at therapeutic doses in the rat is similar to that in patients with osteoporosis who are on treatment with fluoride. In the rat, there is a narrow range between toxic and therapeutic doses.

Abstract True calcium absorption can only be measured by the time-consuming and expensive metabolic balance method and is not predicted well by measuring the fractional absorption (FA) of radiocalcium from a fixed calcium carrier. We describe here a 1 day method for measuring the actual fraction of calcium absorbed from the habitual diet (true fractional calcium absorption, TFCA) using stable isotopes of calcium. Oral and intravenous isotopes were administered with each of the three daily meals, and then the ratio of the two isotopes in the urine was measured by mass spectroscopy. In 12 subjects, TFCA determined from stable Ca correlated well with TFCA measured by the balance method (r = 0.71, P < 0.01), and the mean values were not different (0.26 and 0.26). In contrast, no significant correlation was found between FA and TFCA. The weak relationship between FA and TFCA underscores the importance of tracing dietary calcium rather than a fixed calcium carrier in tests of calcium absorption. Using the new method, TFCA was inversely related to dietary calcium (r = −0.45, P < 0.05), demonstrating that it could detect physiological changes in calcium absorption. Thus, this test has two important advantages: (1) it provides a simple way to measure TFCA and true fractional calcium absorption (the product of TFCA and dietary calcium), the physiologically relevant variables, and (2) because there is no radiation exposure, the test can be used in pregnant women and children, the isotopes can be prepared in advance, and several isotopes can be used simultaneously.